The aging phenotype in humans has been thoroughly studied but a detailed
metabolic profiling capable of shading light on the underpinning biological
processes of longevity is still missing. Here using a combined metabonomics
approach compromising holistic (1)H-NMR profiling and targeted MS approaches, we
report for the first time the metabolic phenotype of longevity in a well
characterized human aging cohort compromising mostly female centenarians,
elderly, and young individuals. With increasing age, targeted MS profiling of
blood serum displayed a marked decrease in tryptophan concentration, while an
unique alteration of specific glycerophospholipids and sphingolipids are seen in
the longevity phenotype. We hypothesized that the overall lipidome changes
specific to longevity putatively reflect centenarians' unique capacity to
adapt/respond to the accumulating oxidative and chronic inflammatory conditions
characteristic of their extreme aging phenotype. Our data in centenarians support
promotion of cellular detoxification mechanisms through specific modulation of
the arachidonic acid metabolic cascade as we underpinned increased concentration
of 8,9-EpETrE, suggesting enhanced cytochrome P450 (CYP) enzyme activity. Such
effective mechanism might result in the activation of an anti-oxidative response,
as displayed by decreased circulating levels of 9-HODE and 9-oxoODE, markers of
lipid peroxidation and oxidative products of linoleic acid. Lastly, we also
revealed that the longevity process deeply affects the structure and composition
of the human gut microbiota as shown by the increased extrection of
phenylacetylglutamine (PAG) and p-cresol sulfate (PCS) in urine of centenarians.
Together, our novel approach in this representative Italian longevity cohort
support the hypothesis that a complex remodeling of lipid, amino acid metabolism,
and of gut microbiota functionality are key regulatory processes marking
exceptional longevity in humans.

The aging phenotype in humans has been thoroughly studied but a detailed
metabolic profiling capable of shading light on the underpinning biological
processes of longevity is still missing. Here using a combined metabonomics
approach compromising holistic (1)H-NMR profiling and targeted MS approaches, we
report for the first time the metabolic phenotype of longevity in a well
characterized human aging cohort compromising mostly female centenarians,
elderly, and young individuals. With increasing age, targeted MS profiling of
blood serum displayed a marked decrease in tryptophan concentration, while an
unique alteration of specific glycerophospholipids and sphingolipids are seen in
the longevity phenotype. We hypothesized that the overall lipidome changes
specific to longevity putatively reflect centenarians' unique capacity to
adapt/respond to the accumulating oxidative and chronic inflammatory conditions
characteristic of their extreme aging phenotype. Our data in centenarians support
promotion of cellular detoxification mechanisms through specific modulation of
the arachidonic acid metabolic cascade as we underpinned increased concentration
of 8,9-EpETrE, suggesting enhanced cytochrome P450 (CYP) enzyme activity. Such
effective mechanism might result in the activation of an anti-oxidative response,
as displayed by decreased circulating levels of 9-HODE and 9-oxoODE, markers of
lipid peroxidation and oxidative products of linoleic acid. Lastly, we also
revealed that the longevity process deeply affects the structure and composition
of the human gut microbiota as shown by the increased extrection of
phenylacetylglutamine (PAG) and p-cresol sulfate (PCS) in urine of centenarians.
Together, our novel approach in this representative Italian longevity cohort
support the hypothesis that a complex remodeling of lipid, amino acid metabolism,
and of gut microbiota functionality are key regulatory processes marking
exceptional longevity in humans.